Benzenesulfonyl ureas

ABSTRACT

BENZENESULFONYL-UREAS HAVING HYPOGLYCEMIC ACTIVITIES CORRESPONDING TO THE FORMULA   1-(R1-NH-CO-NH-SO2-),4-(X-CO-NH-Y-)BENZENE   WHEREIN R1 IS (A) NOCRARAN-7-YL, BICYCLO- 3,1,0!-HEXYL, BICYCLO- 5, 1,0!-OCTYL, OR BICYCLO- 6,1,0!-NONYL; (B) 4,7-ENDOMETHYLENE - PERHYDROINDAN-5-YL; 4,7ENDOMETHYLENE-6-CHLORO-PERHYROINDAN-5-YL; 4,7ENDOMETHYLENE-PERHYDROINDAN - 2 YL; 2,6-ENDOMETHYLENECYCLOHEPTYL; 2,5-ENDOCYCLOBUTYLENE-1,2CYCLOHEXYL; EXO-TRICYCLO-(3,2,1,02,4)-OCTANYL; (C) SPIRO-(2-CYCLOPROPANE) - CYCLOPETYL; SPIRO-(2CYCLOBUTANE)-CYCLOPENTYL; SPIRO-(2-CYCLOPETANE)CYCLOPENTYL; SPIRO-(2-CYLOHEXANE)-CYCLOPENTYL; OR SPIRO-(5,5)-UNDECYL-3; X IS   A,A1-PHENYL OR 3-B,5-A1-THIEN-2-YL   IN WHICH A STANDS FOR HYDROGEN, HALOGEN, RIFLUOROMETHYL, PHENOXY, LOWER ALKYL OR LOWER ALKOXY BOTH HAVING 1-4 CARBON ATOMS, A1 STANDS FOR HYDROGEN, HALOGEN OR LOWER ALKYL OF 1-4 CARBON ATOMS AND B STANDS FOR HYDROGEN OR LOWER ALKOXY HOF 1-4 CARBON ATOMS Y IS A HYDROCARBON CHAIN OF 1-3 CARBON ATOMS OR A PHYSIOLOGICALLY TOLERABLE SALT THEREOF.

United States Patent 3,812,185 BENZENESULFONYL UREAS Helmut Weber,Frankfurt am Main, Walter Aumiiller and Karl Muth, Kelkheim, Taunus, andRndi Weyer, Frankfurt am Main, Germany, assignors to Farbwerke HoechstAktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main,Germany No Drawing. Continuation-impart of applications Ser. No.641,146, May 25, 1967, and Ser. No. 749,609, Aug. 2, 1968, both nowabandoned. This application May 25, 1970, Ser. No. 41,161 Claimspriority, application Germany, May 28, 1966, F 49,329; Apr. 18, 1967, F52,152 Int. Cl. C07c 127/00 US. Cl. 260-553 DA 10 Claims ABSTRACT OF THEDISCLOSURE Benzenesulfonyl-ureas having hypoglycemic activitiescorresponding to the formula wherein R is (a) norcaran-7-yl,bicyclo-[3,1,0]-hexyl, bicycle-[5,

1,0]-octyl, or bicyclo-[6,1,0]-nonyl;

(b) 4,7-endomethylene perhydroindan-S-yl; 4,7-endomethylene-6-chloro-perhydroindan-S-yl; 4,7-endomethylene-perhydroindan 2 yl; 2,6-endomethylenecycloheptyl;2,5-endocyclobutylene-1,2- cyclohexyl; exo-tricyclo-(3,2,l,0 )-octanyl;

(c) spiro-(Z-cyclopropane) cyclopentyl; spiro-(2-cyclobutane)-cyclopentyl; spiro-(2-cyclopentane)- cyclopentyl; spiro-(2-cyclohexane)-cyclopentyl; or spiro-(5,5)-undecyl-3;

Xis

All 8 in which A stands for hydrogen, halogen, trifluoromethyl, phenoxy,lower alkyl or lower alkoxy both having 14 carbon atoms,

A stands for hydrogen, halogen or lower alkyl of 1-4 carbon atoms and Bstands for hydrogen or lower alkoxy of 1-4 carbon atoms Y is ahydrocarbon chain of 1-3 carbon atoms or a physiologically tolerablesalt thereof.

This application is a continuation-in-part of application Ser. No.641,146 filed May 25, 1967 and Ser. No. 749,609 filed Aug. 2, 1968, bothof which are now abandoned.

The present invention relates to benzenesulfonyl-ureas corresponding tothe formula which as such or in the form of their physiologicallytolerable salts particularly their alkali or alkaline earth metal salts,show hypoglycemic properties and are characterized by a strong and longlasting hypoglycemic action. In the formula:

R is

(a) norcaran-7-yl, bicyclo-[3,1,0]-hexyl,

, 3,812,185 Patented May 21, 1974 ice (b) 4,7-endomethyleneperhydroindan-S-yl; 4,7- endomethylene-6-chloro-perhydroindan-5-yl; 4,7-endomethylene perhydroindan-Z-yl; 2,6-endomethylenecycloheptyl;2,5-endocyclobutylene-1,2- cyclohexyl; exo-tricyclo-(Il,2,1,O )-octanyl;

(c) spiro-(2-cyclopropane) cyclopentyl; spiro-(Z-cyclobutane)-cyclopentyl; spiro-(2-cyclopentane)- cyclopentyl;spiro-(Z-cyclohexane)-cyclopentyl; or spiro- (5,5 -undecyl-3;

X is

ll l in which A stands for hydrogen, halogen, trifiuoromethyl, phenoxy,lower alkyl or lower alkoxy both having 1-4 carbon atoms,

A stands for hydrogen, halogen or lower alkyl of l-4 carbon atoms and Bstands for hydrogen or lower alkoxy of 1-4 carbon atoms Y is ahydrocarbon chain of 1-3 carbon atoms or a physiologically tolerablesalt thereof.

According to the above mentioned definitions, halogen may representfluorine, chlorine, bromine or iodine; chlorine and bromine beingpreferred; lower-alkyl or lower alkoxy may represent methyl, ethyl,propyl, isopropyl, n-butyl, tert.-butyl or methoxy, ethoxy, propoxy,isopropoxy, tert.-butoxy, respectively methyl and methoxy beingpreferred.

Ring systems representing the member X in the above mentioned formulaare, for eample, the following:

(LOH; J) CzHs i 3 70 ;CHgCH(CH3)i (iCI-I 20 E;

on, on,

3 H3 CH3 CH3 HEDGE; 0CH3 C i s 1 s s OCH; 0 02H: Hi OHl l 0 s s Asexamples for the bridge member Y there are mentioned:

those binding the benzene nucleus with the carbonamido group over 2carbon atoms are preferred.

The phenylene group mentioned in the formula by is preferablyunsubstituted. It may, however, likewise be monoor polysubstituted byhalogen, lower alkyl or lower alkoxy. It may carry the remaining partsof the molecule in ortho-, metaor para-position to each other, theparaposition being preferred.

The products of the present invention may be prepared by methods wellknown in the benzene-sulfonyl-urea and, for example by reacting abenzene-sulfonyl-isocyanate, -carbamic acid ester, -thiol-carbamic acidester, -carbamic acid halide or -urea substituted by the group with a R-substituted amine.

The reaction products are treated with alkaline agents, if the formationof the salts is desired.

According to the nature of the starting substances in particular of themember X one or the other method for the preparation of certainindividual compounds corresponding to the general formula may beunsuitable in some cases, or, at least require measures for theprotection of active groups. Such cases which do not occur very oftencan easily be recognized by the expert and there will be no difiicultyin applying in these cases another method of synthesis.

As regards the reaction conditions, the forms of realizing the processof the invention may, in general, vary within wide limits and can beadapted to each individual case. For example, the reactions can becarried out with the use of solvents either at room temperature or at anelevated temperature.

The hypoglycemic action of the benzene-sulfonyl-urea derivativesdescribed above could be determined by feeding them to rabbits forexample in the form of sodium salt in doses of 10 mg./kg. anddetermining the blood sugar value according to the known method byHagedorn- Jensen or by means of an autoanalyzer over a prolonged periodof time.

Thus we have found, for example, that 10 mg./kg. of N [4-( 3-2-methoxy-5-methyl-benzamido -ethyl)-benzenesulfonyl]-N'-(4,7-endomethylene perhydro-indanyl- 5)-urea provoke after 3 hours alowering of the blood sugar of 24%. In the same manner, 10 mg. ofN-[4-(fi- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfony1]-N'-(4,7endomethylene-perhydro-indanyl-S)-urea provoke after 6 hours a loweringof the blood sugar of 23%, whereas the knownN-[4-methyl-benzenesulfonyl]- N'-butyl-urea has no blood sugar loweringeffect when administered to rabbits in a dose of less than 25 mg./kg.

Furthermore, we have found that 10 mg. of N-[4-(B- 2 methoxy-benzamidoethyl)-benzenesulfonyl] -N'- (4,7-cndomethylene perhydro indanyl-5)-ureaprovoke after 3 hours a lowering of the blood sugar of 40%.

In the same manner 10 mg./kg. of N-[4-(B- 2-methoxy-5-chlorobenzamidoethyl)-benzenesulfonyl] -N- (exo-tricyclo [3,2,1,0 octane-3-anti)-ureaprovoke after 3 hours a lowering of the blood sugar of 21% which, after24 hours amounts to 23% and after 48 hours still to 17%. When N-[4-(fl-2 methoxy 5 methyl-benzamido -ethyl)-benzenesulfonyl] N (spiro- 5,5-undecyl- 3 -urea is administered to rabbits in a dose of 0.06 mg./kg.,a distinct lowering of the blood sugar can still be observed.

As regards the toxicity of the compounds the values are within the samerange as those of benzenesulfonylureas, for example N-[4-methyl-benzenesulfonyl] -N'-nbutyl urea andN-[4-methyl-benzenesulfonyl]-N-cyclohexyl-urea the LD of which amountsto 2.5 or 4.8 grams/kg. respectively, with oral application.

Hence, the products of the present invention have a very strong bloodsugar lowering action and are extraordinarily well tolerated.

The benzenesulfonyl-ureas of the present invention are preferably usedfor the manufacture of orally administrable pharmaceutical preparationshaving blood sugar lowering action for the treatment of diabetesmellitus and may be used as such or in the form of their physiologicallytolerable salts or in the presence of substances which cause such saltformation. For the formation of salts, there may be used, for example,alkaline agents such as alkali metal hydroxides or alkaline earth metalhydroxides or alkali metal or alkaline earth metal carbonates orbicarbonates, these agents are commonly used in the pharmaceuticalindustry to form physiologically tolerable salts.

The present invention, therefore, also provides phar-= maceuticalpreparations which comprise a benzenesulfonyl-urea of the above generalformula or a physiologically tolerated salt thereof, in admixture orconjunction with a pharmaceutical suitable carrier.

The pharmaceutical preparations are advantageously in the form oftablets and the pharmaceutically suitable carrier may be, for example,talc, starch, lactose, tragacanth or magnesium stearate.

A pharmaceutical preparation, for example a tablet or a powder,containing a benzenesulfonyl-urea of the invention or a physiologicallytolerated salt thereof as the active substance, with or without one ofthe aforementioned carriers, is advantageously brought into a suitableunit dosage form. The dose chosen should comply with the activity of thebenzenesulfonyl-urea or of the physiologically tolerated salt thereofused and the desired effect. Advantageously, the dosage per unit amountsto about 0.5 to mg., preferably 2 to 10 mg., but considerably higher orlower dosage units may also be used, which, if desired, are divided ormultiplied prior to their administration.

The following examples illustrate the invention but they are notintended to limit it thereto:

EXAMPLE 1 N-[4-(fl- 2methoxy 5 chlorobenzamido-ethyl)-benzenesulfonyl]-N-(4,7-endomethylene perhydro-indanyl-S -urea8.5 g. of N-[4-(fi- 2-methoxy-5-chlorobenzamidoethyl)-benzenesulfonyl]-methyl-urethane (melting point 189191 C.) weresuspended in 100 ml. of xylene and after addition of 3.3 g. of5-amino-4,7-endomethyleneperhydro-indan (boilinb point: 96-98 C./8 mm.)(obtained by hydrogenation ofdicyclopentadiene-bis-nitrosochloride/Raney nickel, 100 C. and hydrogenunder a pressure of 100 atmospheres) dissolved in 50 ml. of xylene, thewhole was heated for about 2 hours to 130 C., during which time themethanol which formed during the reaction was separated by distillation.The xylene was removed by distillation under reduced pressure, wherebythe N-[4-(fl- 2-methoxy 5 chlorobenzamido -ethyl)- benzenesnlfonyl]-N'-(4,7-endomethylene perhydro-indanyl-5)-urea that had formedprecipitated. It was recrystallized from methanol. Melting point 196198C.

In analogous manner there were obtained:

from N-[4-(fi- 2-chlorobenzamido -ethyl) benzenesulfonyH-methyl-urethane(melting point: 212-215 C.): the N- [4-( fl- 4-chlorobenzamido -ethyl)-benzenesulfonyl]-N-(4,7-endomethylene perhydro indany1-5)- urea,melting point 206-208" C. (from methanol/dioxane);

from N-[4-(p- 2-methoxybenzamido -ethyl) benzenesulfonyl]-methylurethane (melting point l74176 C.): the N-[4-(;3- 2-methoxybenzamido-ethyl)-benzenesulfonyl]-N-(4,7-endomethylene perhydro-indanyl-5))-urea,melting point 195-197 C. (from methanol from N-[4-(5-2-methoxy-5-methylbenzamido -ethyl)- benzenesulfonyl]-methylurethane(melting point 175 177 C.): the N- [4-(,8- 2-methoxy-5-methylbenzamido-ethyl)-benzenesulfonyl] -N-(4,7 endomethylene-perhydro-indanyl-S)-urea,melting point: 208210 C. (from dilute dioxane);

from N [4 8-benzamido-ethyl -benzenesulfonyl]- methyl urethane (meltingpoint 177-179 C.): the N- [4-(3 benzamidoethyD-benzenesulfonyl]-N'-(4,7- endomethylene-perhydro-indanyl-5)-urea,melting point 218-220 C. (decomposition);

from N [4-(B- 3-trifluoromethyl-benzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 178- 180" C.): theN-[4-([3- 3-trifluoromethyl-benzamido ethyl)-benzenesulfonyl1-N 4,7endomethylene-perhydro-indan-2-yl)-urea, melting point l75l77 C. (frommethanol);

from N [4-(B- 3-chlorobenzamido -ethyl)-benzenesulfonyl]-methylurethane(melting point 173-175 C.): the N-[4-(,8- 3-chlorobenzamido-ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan-2-yl)-urea, melting point 191-192 C. (from methanol); the N [4 (fit- 3chlorobenzamidoethyl)-benzenesulfonyl]-N-(2,6-endomethylene-cycloheptyl)-urea, meltingpoint 186-187 C. (from methanol); the N-[4-(;9- 3 chlorobenzamido-ethyl) benzenesulfonyl]-N- [spiro (2 cyelopentane) cyclopentyl1-urea,melting point 192-193 C.;

from N-[4-(fl- 3-methoxythiophene 2 carbonamidoethyl)-benzenesulfonyl]-methylurethane (melting point 226-228" C.): theN-[4-(f3- 3-methoxythiophene-2- carbonamido ethyl) benzenesulfonyl] N(4,7- endomethylene-perhydro-indan 2 yl) urea, melting point 199-200" C.(from methanol/dimethylformamide);

from N- [4- p 2 methoxy benzamido-ethyl)-benzenesulfonyl]-methyl-urethane (melting point 174-176 C.) theN [4- (13- 2-methoxy-benzamido -ethyl)-benzenesulfonyl] N4,7-endomethylene-perhydro-indan- 2-yl)-urea, melting point 187-189 C.(from methanol/ dimethylformamide); the N-[4-(B- 2-methoxy-benzamido-ethyl)-benzenesulfony1] N (2,6-endomethylene-cycloheptyl)-urea, meltingpoint -172" C. (from methanol); the N [4 (p 2 methoxy-benzamido-ethyl)-benzenesulfonyl] N [spiro-(Z-cyclopentane)-cyclopentyl]-urea,melting point 171172 C.;

from N [4 (fl- 3-methylbenzamido -ethyl)-benzenesulfonyl]-methylurethane(melting point ZOO-202 C.): the N [4 (1 3-methyl-benzamidoethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan-2- yl)-urea,melting point -177 C. (from methanol);

from N-[4-03- Z-methoxy-S-chloro-benzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 189- 191 C.): the N [4([3- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl] N(4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 177- 179 C.(from methanol); the N-[4-(B- 2-methoxy-5- chlorobenzamido-ethyl)-benzenesulfonyl] N (2,6- endomethylene cycloheptyl) urea,melting point 140 142 C. (from methanol);

from N [4- B- Z-methoxy-5-methylbenzamido -ethyl)-=benzenesulfonyl]-methylurethane (melting point 175- 177 C.); the N [4(p- 2-methoxy-5-methylbenzamido -ethyl)-benzenesulfonyl] N(4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 204- 206 C.(from methanol/dimethylformamide); the N- [4 (5 2methoxy-S-methylbenzamido -ethyl)- benzenesulfonyl] N (2,6 endomethylenecycloheptyl)-urea, melting point 189-191" C. (frommethanol/dimethylformamide) from N [4 (B 2 methoxy 5 bromobenzamidoethyl) -benzenesulfonyl] -methylurethane (melting point 197-199 C.): theN-[4-(B- 2-methoxy-5-bromobenzamido -ethyl)-benzenesulfonyl] N(4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 178- C.(from methanol); the N-[4-(fi- 2-methoxy-5- bromobenzamido-ethyl)-benzenesulfonyl] N (2,6- endomethylene-cycloheptyl)-urea,melting point 170- 172 C. (from methanol);

from N [4 (fi- 2-ethoxy-S-chlorobenzamido ethyl)-benzenesulfonyl]-methylurethane (melting point 203- 205 C.); the N [4(,3- 2-ethoxy 5' chlorobenzamido -ethyl) -benzenesulfonyl] N(2,6-endomethylene-cycloheptyl) -urea, melting point 172174 C. (frommethanol);

from N [4 B- 3,5-dimethyl-benzamido-ethyl)-benzenesulfonyl]-methylurethane (melting point 223-225 C.): theN [4 (fl- 3,5-dimethyl-benzamido ethyl)- benzenesulfonyl] N (4,7endomethylene-perhydroindan-2-yl)-urea, melting point 190192 C. (frommethanol);

from N [4 S- 2 methoxy 5 chlorobenzamidoethyl)-benzenesulfonyl]methyl-urethane: the N-[4-(B- 2-methoxy 5chlorobenzamido -ethyl)-benzenesulfonyl] N [spiro (2cyelobutane)-cyclopentyl]- urea, melting point 176-178 C. (frommethanol/dimethylformamide/ water); the N-[4-(;3- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl] -N [spiro-(Z-cyclopropane)-cyclopentyl]-urea, melting point 167 C. (from methanol/dimethylformamide/ water) the N- [4 (13 2 methoxy 5 chlorobenzamido-ethyl)- benzenesulfonyl] N bicyclo [5,1,0] octyl (8)- urea, meltingpoint 150 C. (decomposition) (from methanol/ dimethylformamide/ water);the N- [4- S- 2- methoxy 5 chlorobenzamido ethyD-benzenesulfonyl] N[spiro-(2 cyclopentane) cyclopentyl]- urea, melting point 166168 C.; theN-[4-(,8- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfony1]-N-[2,5-endocyclobutylene (1,2) cyclohexyll-urea, melting point 60 C.;

from N [4 (p- 2-methoxy 5 methyl-benzamidoethyl)-benzenesulfonyl]-methyl-urethane: the N-[4-(fi- 2-methoxy 5methyl-benzamido -ethyl-benzenesulfonyl] N [spiro (2cyclobutane)-cyclopentyl]- urea, melting point 174 C. (frommethanol/dimethylformamide/water; the N-[4-(ti-2-methoxy-5-methylbenzamido -ethy1)-benzene sulfonyl] N -[spiro-(2-cyclopropane)-cyclopentyl]-urea, melting point 188 C. (frommethanol/dimethylformamide/water); the N- [4- (;8- 2-methoxy 5methyl-benzamido -ethyl)-benzenesulfonyl] N [spiro (2cyclopentane)-cyclopentyl]-urea, melting point 201-203 C.;

from N [4 (fit- 3 chlorobenzamido -ethyl)-benzenesulfonyl]-methyl-urethane; the N- [4- (,B- 3-chlorobenzamidoethyl)-benzenesulfonyl] N [spiro- 2-cyclobutane -cyclopentyl]urea,melting point 192 C. (from methanol/ dimethylformamide/ water); theN-[4- (fit- 3 chlorobenzamido ethyl)-benzenesulfonyl]- N- [spiro-2-cyclopropane cyclopentyl]-urea, melting point 187 C. (frommethanol/dimethylformamide/ water);

from N [4 (}8- 2-methoxy-benzamido-ethyl)-benzenesulfonyl]-methyl-urethane: the N [4 B- 2-methoxybenzamido ethyl) benzenesulfonyl] N'- [spiro (2cyclopropane)-cyclopentyl]-urea, melting point 165 C. (frommethanol/water);

from N-[4-(;8- 2-methoxy 5 chlorobenzamid ethyl)- benzenesulfonyl]-methyl-urethane: the N [4 8- 2- methoxy chlorobenzamido ethyl)benzenesulfonylJ-methyl-urethane; the N [4 (fl- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl] N(bicyclo-[3,1,0]-hexyl(6))-urea, melting point 175-177 C. (frommethanol);

from N-[4-(B- 3-chlorobenzamido ethyl) benzenesulfonyl]-methyl-urethane,(melting point 173-175 C): the N-[4-(B- 3 chlorobenzamido ethyl)-benzenesulfonyl]-N'-(spiro- 5.5 undecyl 3 urea, melting point 211-212 C.(from methanol/ dimethylformamide) from N-[4-(ti- 3-methoxythiophene-2carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 226228C): the N-[4-(fi- 3 methoxythiophene 2- carbonamido-ethyl)-benzenesulfonyl] N (spiro- 5.5 -undecyl- 3 )-urea, melting point182183 C. (from methanol);

from N-[4-(B- 2-methoxy-5-methylbenzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 175- 177 C.): theN-[4-(B- 2-methoxy 5 methylbenzamido -ethyl)-benzenesulfonyl]-N' (spiro5.5 undecyl 3 urea (melting point 172-173 C.) (from methanol);

from N-[4-(;8- 2 methoxy 5 bromobenzamido ethyl)-benzenesulfonyl]-methylurethane (melting point 197199 C.): the N-[4-(,3- 2-methoxy 5bromobenzamido -ethyl) benzenesulfonyl] N (spiro- 5.5 -undecyl- 3 urea,melting point 194196 (from methanol/dimethylformamide) from N-[4-(,8-2-phenoxybenzamido -ethyl) benzenesulfonyH-methyl urethane (meltingpoint 167169 C.): the N-[4-(fi- 2 phenoxybenzamido ethyl)-benzenesulfonyl]-N'-(spiro- 5.5 undecyl 3 urea, melting point 166-167 C.(from methanol);

from N- [4- (B- 2-methoxy-4-chlorobenzamido -ethylbenzenesulfonyl]-methylurethane melting point 178- 180 C.): theN-[4-(fi- 2 methoxy 4 chlorobenzamido -ethyl)-benzenesulfonyl]-N' (spiro5.5 undecyl- 3 )-urea, melting point 213-215 C. (frommethanol/dimethylformamide) In analogous manner, there were obtained:

N-[4-(B-Z-methoxy-S-chloro-benzamido-ethyl) benzenesulfonyl-N'-[spiro (2cyclohexane) cyclopentyl]- urea, melting point 152-153 Cs,

N-[4-([3-2-methoxy-S-methyl-benzamido-ethyl) benzenesulfonyl-N' [spiro(2 cyclohexane) cyclopentyl]- urea, melting point 198199 C.;

Fit

N- [4- (13-2-methoxy-benzamido-ethyl) benzenesulfonyl]-N'-[spiro-(Z-cyclohexane)-cyclopentyl] urea, melting point 188-189 C.;

N-[4-(13-3-chloro-benzamido-ethyl) benzene sulfonyl]-N'-[spiro-(2-cyclohexane)-cyclopentyl] urea, melting point 188-190 C.

EXAMPLE 2 N-[4-(}3- 2-methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl]-N-(4,7 endomethylene perhydroindanyl-S -urea A mixtureof 10.3 g. of N-[4-(5- 2-methoxy-5-chlorobenzamidoethyl)-benzenesulfonyl] urea, 300 ml. of toluene, 30 ml. ofglycol-monomethyl ether, 1.65 g. of glacial acetic acid and 4.2 g. of4,7 endomethyleneperhydro-indanyl-S-amine was heated for 5 hours underreflux. The whole was then concentrated under reduced pressure theresidue was treated with alcohol and the crystals obtained, constitutingthe N-[4-(p- 2-methoxy- 5-chlorobenzamido -ethyl)-benzensulfony1] N(4,7- endomethylene-perhydro-indanyl-S)-urea, were recrystallized frommethanol. Melting point 196-198 C.

In analogous manner, there were obtained:

the N-[4-(;8- 2-methoxy-5 chlorobenzamido ethyl)-benzenesulfonyl]-N'-bicyclo-('6,1,0)-nonyl (9) urea, melting point C.(from methanol/dimethylformamide/ water) the N-[4-(;Ei-2-methoxy-S-chlorobenzamido ethyl)- benzenesulfonyl]-N'-(spiro- 5,5undecyl 3 urea, melting point C. (from methanol) and from the N-[4-(;3-2-methoxy-benzamido -ethyl) benzenesulfonyl]-urea, (melting point 183185C.): the N-[4-(p- 2-methoxy-benzamido ethyl) benzenesulfonyl]-N-(spiro-5,5 undecyl 3 urea, melting point 207-209 C. (frommethanol/dimethylformamide).

EXAMPLE 3 N-[4-(fl- 2-methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl]-N'-(4,7 endomethylene perhydroindanyl-S -urea 8.2 g. ofN-[4-(fl-acetamidoethyl) benzenesulfonyl]-N'-(4,7-endomethylene-perhydro-indanyl-S) urea were heated for 2 hoursunder reflux with a solution of 1.6 g. of sodium hydroxide in 30 ml. ofwater. The whole was allowed to cool to room temperature, combined with20 ml. of acetone and 1.3 g. of glacial acetic acid and then, 4.1 g. of2-methoxy-5-chlorobenzoyl chloride were added portionwise. After havingstirred for 2 hours at room temperature the whole was suction-filtered,the precipitate was treated with bicarbonate solution and then dissolvedand reprecipitated from dilute mixture of ammonia and hydrochloric acid.The N-[4- 2-methoxy-5-chlorobenzamido -ethylbenzenesulfonyl]-N'-(4,7endomethyleneperhydro-indanyl-5) urea thus obtained was found to melt,after recrystallization from a mixture of methanol anddimethylformamide, at 196198 C.

EXAMPLE 4 N-[4-(/3- 2-methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl]-N'-(4,7-endomethylene 6 chloroperhydro-ind anyl-S -urea78 g. of N-[4-(B- 2-methoxy-5-chlorobenzamido ethyl) benzenesulfonyl]methylurethane (melting point 189-191 C.) were suspended in 50 ml. ofxylene and combined with 2.7 g. of 4,7-endomethylene 6chloroperhydro-indanyl-S-amine (boiling point 134-138 C./8 mm.). Thereaction mixture was heated for 2 hours to the boiling temperature,during which time the methanol that had formed during the reaction wasdistilled off; after removal by distillation of the xylene under reducedpressure, the residue was treated with strongly diluted sodium hydroxidesolution. Undissolved matter was fil- 9 tered off and the filtrate wasacidified. The N-[4-'(p- 2- methoxy-5-chlorobenzamido -ethyl)benzenesulfonyfl- N'-(4,7-endomethylene-6-chloro-perhydro indanyl 5)-urea thus formed was filtered off with suction and recrystallized fromaqueous dioxane. The substance was found to melt at 189-191 C.;

In analogous manner, there were obtained:

from N-[4-(fl 3-methoxythiophene 2 carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 226-228" C.): theN-[4-(,3- 3-methoxythiophene-2- carbonamido -ethyl) benzenesulfonyl] N(4,7- endomethylene perhydro-indanyl 5) urea, melting point 163-165 C.(from methanol);

from N-[4-(,3- 5-chlorothiophene 2 carbonamidoethyl)-benzenesulfonyl]-methylurethane (melting point 174-176 C.) theN-[4-(13 5- chlorothiophene 2- carbonamido ethyl) benzenesulfonyl] N(4,7- endomethylene-perhydro-indanyl 5) urea, melting point (frommethanol/dirnethylformamide); 190- EXAMPLE 5 N-[4- fi- 2-methoxy 5chlorobenzamido ethyl)- benzenesulfonyl]-N-(exo-tricyclo [3,2,1,0]-octane- 3-anti)-urea N-[4-(;3- 2-methoxy benzamidoethyl)-benzene-sulfonyl] N (oxotricyclo [3,2,1,0 ]-octane-3-anti)- urea,melting point 186-188 C.;

N- [4- (fl- 2-methoxy 5 methylbenzamido -ethyl)-benzenesulfonyl] N(oxotricyclo-[3,2,1,0 ]-octane-3- anti)-urea, melting point 175-177 C.(decomposition);

N [4-( fl- 4 chloro benzamido -ethyl)-benzene-sulfonyl]-N(oxo-tricyclo-[3,2,-1, ]-octane-3-anti)-urea, melting point 202-204" C.(decomposition).

EXAMPLE 6 N-[4 (fi- 2 methoxy chlorobenzamido -ethyl)-benzenesulfonyH-N' (4,7 endomethylene-perhydroindanyl-S -urea 5 g. of4-(B- 2 methoxy 5 chlorobenzamido ethyl)-benzenesulfonamide weredissolved in 7 ml. of binormal sodium hydroxide solution and 50 ml. ofacetone and to this solution, there were added dropwise, while stirringand at 0-5 C., 2.7 g. of 4,7-endomethyleneperhydro-indanyl-S-isocyanate.The whole was stirred for 3 hours, diluted with water and methanol,undissolved matter was filtered ofl? and the filtrate was acidified withdilute hydrochloric acid. The N-[4-(/3- 2-methoxy-5- chlorobenzamido-ethyl)-benzenesulfonyl] N (4,7- endomethylene-perhydro-indanyl-S)-ureathat had precipitated was found to melt, after recrystallization frommethanol, at 196-198 C.

In analogous manner, there were obtained: from 4-( S-3,4-dichlorobenzamido -ethyl)-benzenesulfonamide (melting point 171-172C.).

Furthermore, there were prepared in a manner analogous to that ofExample 6: the N-[4-(B- 2-methoxy 5 chlorobenzamido-ethylbenzenesulfonyl]-N'-norcaran-7-yl-urea, melting point 158 C. (frommethanol/water);

from 4-(fl- 2-methoxy 5 methylbenzamido -ethyl)- benzenesulfonamide(melting point 197 C); the N- [4 (B- 2-methoxy 5 methylbenzamido-ethyl-benzenesulfonyl]-N'-norcaran-7-yl-urea, melting point 183' C.(from methanol/ water);

from 4-(fl- 4 chlorobenzamido -ethyl)benzenesulfonamide (melting point225 C.) the N-[4-(B- 4-chlorobenzamido ethyl)benzenesulfonyl]-N-norcaran-7- yl-urea, melting point 137 C. (frommethanol/water).

EXAMPLE 7 N [4 (fi- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl]-N 4,7 endomethylene-perhydroindanyl-S -urea 1 g. ofN-[4-(,9- 2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonyl]-N'(4,7-endomethylene-perhydro-indanyl-5)-thiourea (melting point 137-l39C.) was dissolved in ml. of methanol which had been combined with 10 ml.of dioxane. 1.1 g. of mercury oxide was added and the whole was stirredfor three hours at 50-60" C. After removal of the mercury sulfide byfiltration, the whole was concentrated under reduced pressure. The N-[4(ti- 2 methoxy 5 chlorobenzamido ethyl)-benzene-sulfonyl]-N'(4,7-endomethylene-perhydro-indanyl-5)-isourea methyl ether thusobtained was suspended in 20 ml. of dioxane and 100 ml. of concentratedhydrochloric acid. The whole was heated for 10 minutes on the steambath, poured into water, the precipitate was filtered oif with suctionand recrystallized from methanol.

The N-[4 (fi- Z-methoxy-S-chlorobenzamido ethyl)-benzenesulfonyl]-N (4,7endomethylene-perhydro-indanyl-5)-urea was found to melt at 196-198 C.

EXAMPLE 8 N [4 (fl- 2-methoxy-5-chlorobenzamido -ethy1)-benzenesulfonyH-N' (4,7 endomethylene-perhydro indanyl-S -urea 1 g. ofN-[4- 2-methoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl]-N (4,7endomethylene-perhydroindanyl-5)-thio-urea (melting point 137-139 C.)were suspended in 20 ml. of binormal sodium hydroxide solution andcombined with 5 ml. of hydrogen peroxide having a strength of 5%.

The whole was heated for 15 minutes on the steam bath, cooled andacidified. A precipitate was obtained which was filtered oil? withsuction and washed with water. The N- [4 (18-2-methoxy-5-chlorobenzamido-ethyl)-benzenesulfonyl]-N-(4,7-endomethylene-perhydro-indanyl 5)- ureathus obtained was found to melt, after recrystallization from a mixtureof methanol and dioxane, at 196- 198 C.

EXAMPLE 9 N [4 (pi- 3 methoxy 5 chloro-thiophene 2- carbonamido-ethyl)-benzenesulfonyl] N (4,7- endomethylene-perhydro-ind anyl-S -urea6.48 g. of N-[4-(fi- 3-rnethoxy-5-chloro-thiophene-2- carbonamidoethyl)-benzenesulfonyl]-methylurethane (melting point 189-19l C.)together with 2.26 g. of 5- amino-4,7-endomethylene-perhydro-indan and300 ml. of dioxane were heated for 1 hour to the boiling temperatureunder reflux. After removal of the solvent by distillation under reducedpressure, the residue obtained was treated with strongly dilutedammonia, filtered and the filtrate was acidified. The precipitateobtained was filtered off with suction and recrystallized from methanol.The N- [4- (fl- 3-methoxy-S-chlorothiophen-Z-carbonamidoethyl)-benzenesulfonyl]-N' (4,7 endomethylene-perhydro-indanyl-5)-ureathus obtained. was found to melt at 181-183 C.

In analogous manner, there was obtained:

from N-[4-(;3- 5-chloro-thiophene 2 carbonamidoethyl)-benzenesulfonyl]-methylurethane (melting point 174-176 C.): the N[4 (B- 5-chloro-thiophene-2- carbonamido ethyl) benzenesulfonyl] N (4,7-endomethylene-perhydro-indanyl-5)-urea, melting point 190-l92 C. (frommethanol/water).

We claim:

1. A benzenesulfonyl-urea corresponding to the formula A stands forhydrogen, halogen, trifiuoromethyl,

phenoxy, lower alkyl or lower alkoxy both having 20 1-4 carbon atoms, Astands for hydrogen, halogen or lower alkyl of 1-4 carbon atoms and Y isa saturated hydrocarbon chain of 1-3 carbon atoms or a salt thereof of apharmaceutically acceptable base.

2. The compound of claim 1 wherein X is CH: 3. The compound of claim 1wherein X is 4. The compound of claim 1 wherein Y is CH CH 5. Thecompound of claim 1 wherein 3 is -Q- 6. The compound of claim 1 whereinX is phenyl which is substituted in 2-positiou by lower alkoxy.

7. The compound of claim 1 wherein X is phenyl which is substituted in2-position by lower alkoxy and in 4- or 5- position by halogen, loweralkyl or alkoxy.

8. The compound of claim 1 wherein X is phenyl which is substituted in2-position by methoxy and in 4- or 5- position by halogen, methyl ormethoxy.

9. The compound of claim 1 wherein X is phenyl which is substituted in2-position by methoxy and in 4- or 5- position by chlorine.

10. The compound of claim 1, wherein X is Z-methoxy- S-methyl-phenyl, Yis --CH -CH and R is 2,6-endomethylene-cycloheptyl.

References Cited UNITED STATES PATENTS 3,426,067 2/ 1969 Weber et a1260553 DA 3,183,260 5/1965 Loev 260553 D 3,454,635 7/1969 Wc'ber et al260553 DA BERNARD HELFIN, Primary Examiner G. A. SCHWARTZ, AssistantExaminer US. Cl. X.R.

